Aperçu: G.M.
L'ensemble des résultats indique que les deletions de Shank1 conduisent à un
phénotype cognitif aberrant caractérisé par des déficiences graves dans
la mémoire de reconnaissance d'objet et l'augmentation des taux de BDNF
hippocampiques, éventuellement à cause de modifications épigénétiques.
Ce
résultat confirme le lien entre TSA et handicap intellectuel, et
suggère une régulation épigénétique comme cible thérapeutique
potentielle.
Hippocampus. 2017 May 12. doi: 10.1002/hipo.22741.
Aberrant cognitive phenotypes and altered hippocampal BDNF expression related to epigenetic modifications in mice lacking the post-synaptic scaffolding protein SHANK1: Implications for autism spectrum disorder
Sungur AÖ1, Jochner MCE1, Harb H2, Kılıç A2, Garn H2, Schwarting RKW1, Wöhr M1.
Author information
- 1
- Behavioral Neuroscience, Experimental and Biological Psychology, Philipps-University of Marburg, Marburg, Germany.
- 2
- Institute of Laboratory Medicine and Pathobiochemistry-Molecular Diagnostics, Philipps-University of Marburg, Marburg, Germany.
Abstract
Autism
spectrum disorder (ASD) is a class of neurodevelopmental disorders
characterized by persistent deficits in social
communication/interaction, together with restricted/repetitive patterns
of behavior. ASD is among the most heritable neuropsychiatric
conditions, and while available evidence points to a complex set of
genetic factors, the SHANK gene family has emerged as one of the most
promising candidates. Here, we assessed ASD-related phenotypes with
particular emphasis on social behavior and cognition in Shank1 mouse
mutants in comparison to heterozygous and wildtype littermate controls
across development in both sexes. While social approach behavior was
evident in all experimental conditions and social recognition was only
mildly affected by genotype, Shank1-/- null mutant mice were
severely impaired in object recognition memory. This effect was
particularly prominent in juveniles, not due to impairments in object
discrimination, and replicated in independent mouse cohorts. At the
neurobiological level, object recognition deficits were paralleled by
increased brain-derived neurotrophic factor (BDNF) protein expression in
the hippocampus of Shank1-/- mice; yet BDNF levels did not
differ under baseline conditions. We therefore investigated changes in
the epigenetic regulation of hippocampal BDNF expression and detected an
enrichment of histone H3 acetylation at the Bdnf promoter1 in Shank1-/-
mice, consistent with increased learning-associated BDNF. Together, our
findings indicate that Shank1 deletions lead to an aberrant cognitive
phenotype characterized by severe impairments in object recognition
memory and increased hippocampal BDNF levels, possibly due to epigenetic
modifications. This result supports the link between ASD and
intellectual disability, and suggests epigenetic regulation as a
potential therapeutic target. This article is protected by copyright.
All rights reserved.
© 2017 Wiley Periodicals, Inc.
- PMID: 28500650
- DOI: 10.1002/hipo.22741
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